[0001] The present invention relates to a pharmaceutical composition containing at least
one polysaccharide in aqueous solution, of the type which undergoes liquid-gel phase
transition under the effect of an increase in the ionic strength.
[0002] The pharmaceutical compositions of the invention are of the type which undergoes
liquid-gel phase transition under the effect of an increase in the ionic strength.
[0003] They are particularly intended for contacting with physiological liquids. Thus the
transition occurs at the contact, as the physiological liquids have a higher tonicity
than the one of said compositions.
[0004] The compositions of the invention are specially useful for ophtalmic use, but also
as injectable form, the formed gel having thus the function of slow-release form,
as by intradermic or intramuscular injections, or as galenic form intended for contacting
with mucous membranes.
[0005] A large percentage of drugs administered to the eye is lost as a result of lacrimal
drainage ; this applies especially in the case of a liquid formulation. In effect,
as a result of this drainage, only a small fraction of the dose administered remains
in contact with the cornea for a few minutes, and an even smaller fraction penetrates
into the eye.
[0006] To overcome this disadvantage, it is known to use viscous solutions, gels, eye ointments
or solid eye implants.
[0007] Progress has been made in the delivery of drugs by the use of these galenical forms,
especially by using the solid implants, by means of which it is possible to reduce
greatly the doses of active principle in the formulation while retaining a therapeutic
response equivalent to that which would be induced by an eye lotion, the latter, in
addition, needing to be administered more frequently.
[0008] Some of these implants function by diffusion. Thus, for example, in the "OCUSERT
®" system, one weekly application of an oval lens in the conjunctival sac enables
an active principle to be delivered by diffusion, but this lens has to be removed
after use, which is a source of problems for the patients.
[0009] Other function by dissolution, and, in this case, since the implants are either soluble
or autodegradable ("LACRISERT ®" system), their duration of action is much shorter.
[0010] In all cases, the solid implants possess a major disadvantage in that many patients
find it difficult to tolerate the introduction into the conjunctival culs-de-sacs
of the solid object represented by this implant.
[0011] To solve this problem, galenical forms can be used which are liquid at room temperature
and assure a semi-solid form at human body temperature. Such delivery systems are
described in US Patent 4,188,373, which propose the use of "PLURONIC ® polyols".
[0012] These "PLURONIC ® polyols" are thermally gelling polymers in which the polymer concentration
is chosen in accordance with the desired liquid-gel transition temperature.
[0013] However, with the commercially available "PLURONIC® polymers", it is difficult to
obtain a gel of suitable rigidity while maintaining the transition temperature at
physiological temperatures, which are of the order of 25° C - 36° C.
[0014] Similarly, Canadian Patent 1,072,413 describes systems containing a therapeutic
or other agent (poloxamer), the gelification temperatures of which are made higher
than room temperature by using additives.
[0015] The thermally gelling systems have many disadvantages, including the risk of gelling
before administration by an increase in the ambient temperature during packaging or
storage, for example.
[0016] US Patent 4,474,751 of Merck & Co., relates to other systems for delivering drugs
based on thermogelification of gels, but these systems require very large amounts
of polymers and this is not always well tolerated by the eye.
[0017] The present invention relates to a pharmaceutical composition intended for contacting
with a physiological liquid characterized in that said composition is intended to
be administered as a non-gelled liquid form and in intended to gel in situ, this
composition containing at least one polysaccharide in aqueous solution, of the type
which undergoes liquid-gel phase transition gelling in situ under the effect of an
increase in the ionic strength of said physiological liquid.
[0018] The preferred pharmaceutical composition according to the invention is an ophthalmological
composition, the physiological liquide being the lacrimal fluid. Thus, the present
invention overcomes these particular problems of administering ophthalmic compositions.
[0019] As a matter of fact, the composition, which takes the form of a liquid before its
introduction into the eye, undergoes a liquid-gel phase transition, and hence changes
from the liquid phase to the gel phase, once it is introduced into the eye, as a
result of the ionic strength of the physiological fluid which is in this case, the
lacrimal fluid.
[0020] This new ophthalmological composition is an amazingly advantageous form for several
reasons. In particular, since the presence of lacrimal fluid is required to induce
gel formation, any accidental spillage of solution outside of the eye cannot result
in gel formation. Furthermore, in contrast to the thermally gelling systems, an increase
in the ambient temperature cannot result in the solution gelling during storage.
[0021] Also, the polymer used can form a gel at concentrations 10- to 100- fold lower than
those used in systems involving thermogelification. It is hence very well tolerated
by the eye.
[0022] Finally, when these compositions contain a pharmaceutically active substance, such
a delivery system makes it possible to achieve great bioavailability of the product,
and concentrations of active principle which are sustained with time, advantages of
a slow delivery system.
[0023] Furthermore, in the case of already gelled or semi-solid compositions, it is not
possible to administer them by volumetric means, especially when they come from a
multi-dose container. To administer these in reproducible quantities, one is then
compelled to employ gravimetric means.
[0024] The compositions according to the invention have, on the one hand, the advantage
of liquid ophthalmic compositions, namely reproducible and accurate dosing, by volumetric
means, of the active substance, and on the other hand the advantages known for the
systems in rigid or semi-solid gel form, relating to the delivery of active substances.
[0025] The composition according to the invention consequently has neither the disadvantages
of losses of active substances characteristic of simple liquid compositions, nor the
unpleasant aspects of solid implant systems, nor finally the difficulties of administration
associated with gelled or semi-solid compositions.
[0026] The Applicant Company has demonstrated that aqueous polysaccharide solutions, of
the type which undergoes liquid-gel phase transition under the effect of an increase
in the ionic strength, and are especially suitable according to the invention, are
solutions of a polysaccharide obtained by fermentation of a microorganism.
[0027] Thus, according to the invention, an extracellular anionic heteropolysaccharide elaborated
by the bacterium Pseudomonas elodea and known by the name gellan gum is preferably
used.
[0028] This polysaccharide, manufactured by KELCO & Co., is already used as a gelling agent
for culture medium and also in food products. The structure of this heteropolysaccharide
consists of the following tetrasaccharide repeating unit :
→3)-β-D-Glcp-(1→4)-β-D-GlcpA-(1→4)-β-D-Glcp-(1→4)-α-L-Rhap-(1→
which may, or may not, be partially 0-acetylated on its β-D-glucopyranose (β-D-Glcp)
residues.
[0029] The preparation of such polysaccharides in native and deacetylated form is described,
in particular, in Patents US 4,326,053 and 4,326,052 of MERCK & CO., Inc. Rahway N.J.,
and their structure has been described, in particular, by JANSSON & LINDBERG, Carbohydr.
res. 124 (1983) 135-9.
[0030] According to the present invention, aqueous solutions containing about 0.1 % to
about 2.0 % by weight of gellan gum, and especially of the product known by the tradename
Gelrite ®, which is a low acetyl clarified grade of gellan gum, are viscous at low
ionic strength but undergo a liquid-gel transition when the ionic strength is increased,
and this is the case when this aqueous solution is introduced into the eye.
[0031] The rigidity of the gel can be modified by ajusting the polymer concentration.
[0032] The gellan gum product not only has the property of changing form the liquid to the
solid phase when placed in a medium of higher ionic strength, but it also prossesses
two advantageous additional properties according to the present invention.
[0033] In effect, Gelrite ® in aqueous solution is thixotropic (Figure 1) and thermoplastic
(Figure 2).
[0034] These two properties enable its fluidity to be increased by shaking or slightly
warming the sample before administration to the eye.
Figure 1 shows the rheology of a 0.6 % aqueous solution of Gelrite ® at 20° C (shear
stress (Pa) versus shear rate (Sec⁻¹)).
Figure 2 shows the shear stress (Pa) versus temperature (° C) behavior [at a constant
shear rate of 86 second⁻¹] of a 0.6 % Gelrite ® solution, after a 30 % dilution :
1) in distilled water ;
2) in a simulated tear fluid.
[0035] This latter case of Figure 2 2) shows the increase in viscosity resulting from the
dilution of Gelrite ® in a simulated lacrimal fluid.
[0036] Thus, the Applicant Company has demonstrated gel formation in a rabbit's eye following
a 20 µl instillation of a solution containing 0.4 % by weight of Gelrite ® in deionized
water.
[0037] The ophthalmic compositions according to the invention can be used as they are in
various applications, and, for example, to maintain adequate hydration of the eye
(treatment of dry eye syndrome).
[0038] Furthermore, it appears that the ophtalmic compositions according to the invention
are especially suitable for administering to the eye any pharmaceutically active substance
administered for curative and/or diagnostic purposes. Thus, the present invention
relates to a pharmaceutical composition which contains at least one pharmaceutically
active substance for curative or diagnostic purposes.
[0039] By pharmaceutically active substance, there is understood one or more drugs and/or
one or more diagnostic agents. Any active susbtance can be delivered by the compositions
according to the invention. The active substance is preferably chosen to be soluble
in water, although some active substances show greater solubility than others in the
aqueous polysaccharide solutions according to the invention. Furthermore, active
substances can be in suspension or in emulsion (e.g. emulsions of oil droplets, complex
lipidic materials, liposomes) in the aqueous polysaccharide solutions. Therefore,
the present invention relates to ophthalmic compositions containing at least one
active substance in solution or suspension or emulsion in the aqueous polysaccharide
solution.
[0040] The prefered pharmaceutically active substance, used according to the present invention
is timolol or one of its derivatives.
[0041] Timolol can be used alone or in combination with other pharmaceutically active agents.
[0042] The present invention relates to the ophthalmic compositions preferably containing
about 0.1 % to about 2.0 % by weight of the polysaccharide described above, and about
0.001 % to about 5 % by weight of at least one pharmaceutically active substance.
[0043] The quantities relating to the aqueous gellan gum solution make it possible to obtain
a suitable gel consistency and to compensate the loss induced by the sterilization
procedures used during the process of manufacture of these ophthalmic compositions.
[0044] Other additives can also take part in the ophthalmic compositions according to the
invention. These are, in particular, other polymers suitable for topical application
to the eye, small amounts of acids or bases for adjusting the pH to values suitable
for administration to the eye, nonionic tonicity adjusting agents, surfactants, agents
for controlling bacterial contamination or, for example, other additives for solubilization
or stabilization of the active substance, or any other additive which assist in the
formulation.
[0045] If necessary, the gel-inducing effect of ionized active substances, for example,
which are incorporated in the compositions according to the invention, can be neutralized
by adding to the formulation a suitable ion pair-forming agent.
[0046] For example, the slight gelling effect induced by adding 0.1 mg/ml of benzalkonium
chloride in a Gelrite ® solution according to the invention can be eliminated by adding
a small amount of acetic acid. The Applicant Company has in addition demonstrated
that Gelrite ® solutions according to the invention are compatible with other formulation
ingredients such as various buffers and potential ion pair-forming agents.
[0047] As will emerge in the examples, mannitol can be used in the compositions according
to the invention in order to regulate the tonicity of the medium without changing
the gelling properties.
[0048] Other tonicity adjusting agents can be used, sorbitol or any sugar for example.
[0049] For their administration to the eye, the ophthalmic compositions according to the
invention are administered in liquid form, by any conventional means for delivering
drops, such as an eye-dropper or, for example, the socalled "OCUMETER ®" system.
[0050] The compositions according to the invention can be administered in the usual manner
for eye lotions, in the inferior cul-de-sac of the conjunctiva on the outside of the
eye.
[0051] By way of example, a drop of liquid composition containing about 25 mg of ophthalmic
composition enables about 0.0025 mg to about 1.25 mg of active substance to be administered.
[0052] The active substances, or drugs, or diagnostic agents, used in the pharmaceutical
compositions according to the invention are preferably suited to the treatment of
the disease from which the patient is suffering and/or to the diagnostic method which
it is desired to employ.
[0053] For example, if the patient is suffering from glaucoma, the active substance chosen
in preferably a beta-blocker such as timolol or one of its derivatives.
[0054] Toxicological studies prove the good tolerability of gellan gums : acute oral toxicity
tests in rats show that the lethal dose 50 (LD₅₀) is greater than 5000 mg per kg ;
acute toxicity tests by inhalation show that exposure of rats for 4 hours to a nominal
concentration of 6.09 mg/l does not cause the death of any animal in a group of 10
animals, which indicates that the lethal concentration 50 (LC₅₀) is greater than 6.09
mg/l.
[0055] DRAIZE-type eye irritation tests in rabbits show that the product is not regarded
as an eye irritant.
[0056] When these compositions contain an active substance, the objective of such a system
for delivering the active substance is to achieve great bioavailability of the substance
and concentrations of this substance which are sustained with time.
[0057] The drugs or diagnostic agents which can be administered by means of the ophthalmic
compositions according to the invention are, for example :
antibacterial substances such as beta-lactam antibiotics, such as cefoxitin, n-formamidoylthienamycin and
other thienamycin derivatives, tetracyclines, chloramphenicol, neomycin, carbenicillin,
colistin, penicillin G, polymyxin B, vancomycin, cefazolin, cephaloridine, chibrorifamycin,
gramicidin, bacitracin and sulfonamides ;
aminoglycoside antibiotics such as gentamycin, kanamycin, amikacin, sisomicin and
tobramycin ;
nalidixic acid and its analogs such as norfloxacin and the antimicrobial combination fluoroalanine/pentizidone,
nitrofurazones and analogs thereof ;
antihistaminics and decongestants such as pyrilamine, chlorpheniramine, tetrahydrazoline, antazoline and analogs thereof
;
anti-inflammatories such as cortisone, hydrocortisone, hydrocortisone acetate, betamethasone, dexamethasone,
dexamethasone sodium phosphate, prednisone, methylpredni solone, medrysone, fluorometholone,
prednisolone, prednisolone sodium phosphate, triamcinolone, indomethacin, sulindac,
its salts and its corresponding sulfides, and analogs thereof ;
miotics and anticholinergics such as echothiophate, pilocarpine, physostigmine salicylate, diisopropylfluorophosphate,
epinephrine, dipivaloylepinephrine, neostigmine, echothiopate iodide, demecarium bromide,
carbamoyl choline chloride, methacholine, bethanechol, and analogs thereof ;
mydriatics such as atropine, homatropine, scopolamine, hydroxyamphetamine, ephedrine, cocaine,
tropicamide, phenylephrine, cyclopentolate, oxyphenonium, eucatropine, and analogs
thereof ;
other drugs used in the treatment of conditions and lesions of the eyes such as :
antiglaucoma drugs for example timolol, and especially its maleic salt and R-timolol
and a combination of timolol or R-timolol with pilocarpine, as well as many other
adrenergic agonists and/or antigonists ; epinephrine and an epinephrine complex, or
prodrugs such as bitartrate, borate, hydrochloride and dipivefrine derivatives and
hyperosmotic agents such as glycerol, mannitol and urea ; carbonic anhydrase inhibitors
such as acetazolamide, dichlorphenamide, 2-(p-hydroxyphenyl)-thio-5thiophenesulfonamide,
6-hydroxy-2-benzothiazolesulfonamide and 6-pivaloyloxy-2-benzothiazolesulfonamide
;
antiparasitic compounds and/or anti-protozoal compounds such as ivermectin, pyrimethamine, trisulfapidimidine, clindamycin and corticosteroid
preparations ;
compounds having antiviral activity such as acyclovir, 5-iodo-2'-deoxyuridine (IDU), adenosine arabinoside (Ara-A),
trifluorothymidine, and interferon and interferon-inducing agents such as poly I :
C ;
antifungal agents such as amphotericin B, nystatin, flucytosine, natamycin and miconazole ;
anesthetic agents such as etidocaine cocaine, benoxinate, dibucaine hydrochloride, dyclonine hydrochloride,
naepaine, phenacaine hydrochloride, piperocaine, proparacaine hydrochloride, tetracaine
hydrochloride, hexylcaine, bupivacaine, lidocaine, mepivacaine and prilocaine ;
ophthalmic diagnostic agents, such as :
a) those used to examine the retina such as sodium fluorescein ;
b) those used to examine the conjunctiva, cornea and lacrimal apparatus, such as
fluorescein and rose bengal ; and
c) those used to examine abnormal pupillary responses such as methacholine, cocaine,
adrenaline, atropine, hydroxyamphetamine and pilocarpine ;
ophthalmic agents used as adjuncts in surgery, such as alpha-chymotrypsin and hyaluronidase ;
chelating agents such as ethylenediaminetetraacetic acid (EDTA) and deferoxamine ;
immunosuppressants and anti-metabolites such as methotrexate, cyclophosphamide, 6-mercaptopurine and azathioprine ; and
combinations of the compounds mentioned above, such as antibiotics/antiinflammatories
combinations such as the combination of neomycin sulfate and dexamethasone sodium
phosphate, and combinations concomitantly treating glaucoma, for example a combination
of timolol maleate and aceclidine.
[0058] Generally, the tears produced by the eye dilute the active substance and very rapidly
deplete the dose of active substance administered by conventional liquid solutions.
[0059] The compositions containing a polysaccharide in aqueous solution according to the
invention, of the type which undergoes liquid-gel phase transition under the effect
of an increase in the ionic strength, are diluted less rapidly and make it possible
to obtain a sustained delivery of the active substance dissolved or suspended in the
composition. (To this end, the total ionic strength of the formulation must be kept
as low as possible). This prolonged residence time, permitted by the composition according
to the present invention, leads to more effective levels of concentration of active
substance in the lacrimal film.
[0060] A test which demonstrates the prolonged presence of the active substance after instillation
in the eye of a composition according to the invention, and also other characteristics
and advantages of the present invention, appear in the Examples and Figures which
follow, which illustrate the invention (the percentages being given by weight).
EXAMPLE 4 :
[0061] To demonstrate the prolonged presence of the active substance in the eye, after
instillation of the active substance incorporated in a composition according to the
invention, a comparative test was performed.
[0062] The removal of fluorescein from the conjunctival sac of rabbits after an instillation
of fluorescein solution, either in distilled water or in a vehicle containing 0.6
% Gelrite ® , was observed by far UV radiation.
[0063] In the eyes treated with the aqueous solution, no fluorescein remains 3 hours afer
the instillation, whereas in the eyes treated with the vehicle containing the Gelrite
® , fluorescein is still persisting 5 hours after the instillation.
EXAMPLE 5 :
Composition for delivering timolol
[0064] Studies are carried out in vivo to obtain data concerning the timolol bioavailability
from the solution 1 of example 2. The concentration of timolol in aqueous humor of
non-anaesthetized Albino Rabbits is valued. Single 50 µl Instillations of Gelrite
® Formulations (Example 2 solution 1) and Timoptic ® commercial solutions, each Containing
0.25 % of timolol are carried out for a comparison purpose. The Gelrite ® Solutions
were Made with 3 Different lots of Gelrite ®Polymers.
The obtained results are shown in the following table :
[0065] The invention is not limited to the above examples ; the compositions of the invention
are also useful for their application in all pharmaceutical compositions, which are
intended for contacting with the physiological liquids.
[0066] Thus, the present invention also concerns the injectable compositions, for intradermic
or intramuscular injections, and external topical compositions which are intended
for contacting with mucous membranes.
1. Pharmaceutical composition intended for contacting with a physiological liquid
characterized in that said composition is intended to be administered as a non-gelled
liquid form and is intended to gel in situ, this composition containing at least one
polysaccharide in aqueous solution, of the type which undergoes liquid-gel phase transition
gelling in situ under the effect of an increase in the ionic strength of said physiological
liquid.
2. Pharmaceutical composition as claimed in claim 1 characterized in that said composition
is an ophthalmological composition, the physiological liquid being the lacrimal
fluid.
3. Composition as claimed in claim 1 or 2, in which the polysaccharide is obtained
by fermentation of a microorganism.
4. Composition as claimed in claim 3 in which the microorganism is Pseudomonas elodea.
5. Composition as claimed in claim 1 or 2, in which the polysaccharide has as its
basic tetrasaccharide unit →3)-β-D-Glcp-(1→4)-β-D-GlcpA-(1→4)-β-D-Glcp-(1→4)-α-L-Rhap-(1→
which may, or may not, be partially 0-acetylated on its β-D-glycopyranosyl residues.
6. Composition as claimed in one of claims 1 to 5, which contains 0.1 to 2.0 % by
weight of the said polysaccharide.
7. Composition as claimed in one of claims 1 to 6, which contains in addition a tonicity
adjusting agent.
8. Composition as claimed in claim 7, in which the tonicity adjusting agent is a sugar
such as mannitol or sorbitol.
9. Composition as claimed in one of claims 1 to 8, which contains at least one pharmaceutically
active substance for curative or diagnostic purposes.
10. Composition as claimed in claim 9, in which the pharmaceutically active substance
is timolol or a derivative thereof.
11. Composition as claimed in claim 9 or 10, which contains 0.1 to 2.0 % by weight
of polysaccharide and 0.001 to 5 % by weight of at least one pharmaceutically active
substance for curative or diagnostic purposes.
12. Composition as claimed in one of claims 1 to 11 in which the pharmaceutically
active substance is in solution.
13. Composition as claimed in one of claims 1 to 11 in which the pharmaceutically
active substance is in suspension.
14. Composition as claimed in one of claims 1 to 11 in which the pharmaceutically
active substance is in emulsion.
15. Ophthalmic composition as claimed in one of claims 1 to 14.
16. Injectable composition as claimed in one of claims 1 to 14.
17. Composition for application to mucous membrane as claimed in one of claims 1 to
14.